Background Information
 

Specific information is included on the following subjects:

• Treatment of established Cytomegalovirus disease

• Evidence for the clinical efficacy of prophylaxis and pre-emptive therapy in solid organ transplant recipients

• Evidence for the clinical efficacy of prophylaxis and pre-emptive therapy in bone marrow transplant recipients

• Recent developments in understanding cytomegalovirus replication, dynamics and resistance

• Comparison and availability of diagnostic assays for cytomegalovirus detection in transplant recipients

For more information, see the monograph:

The Challenge of CMV Infection and Disease in Transplantation

• In any transplant recipient, cytomegalovirus (CMV) disease should be treated for 2–4 weeks with intravenous ganciclovir (Category 2 recommendation)*

• Bone marrow transplant (BMT) recipients with pneumonitis should be treated with intravenous ganciclovir plus polyvalent immune globulin (IVIG) or CMV hyper immune globulin (CMVIG) (Category 2 recommendation)

• Aciclovir is not effective in treating established CMV disease in transplant recipients (Category 2 statement)

• It is unclear whether the addition of polyvalent IVIG or CMVIG to existing treatment regimens has a benefit for solid organ transplant recipients or for diseases other than pneumonitis in BMT patients (Category 3 statement )

• Oral ganciclovir should not be used to treat established CMV disease (Category 3 recommendation )

• Combination therapy with foscarnet and ganciclovir should be fully investigated in randomized, controlled trials (Research need recommendation ).

For more information, see the monograph:

The Challenge of CMV Infection and Disease in Transplantation

Prophylaxis
Ganciclovir

• For heart transplant recipients, intravenous ganciclovir reduced the incidence of cytomegalovirus (CMV) disease in CMV-seronegative patients (R–) in one study and in CMV-seropositive recipients (R+) in a second trial (Category 1 statement)

• Oral ganciclovir reduces the incidence of CMV disease in liver transplant recipients (Category 1 statement)

• In addition to effects on CMV disease, the incidence of herpes simplex virus (HSV) disease is reduced by intravenous ganciclovir in heart and liver transplant recipients and by oral ganciclovir in liver transplant recipients (Category 1 statement)

• Intravenous ganciclovir is more effective in reducing the incidence of CMV disease than intravenous aciclovir followed by oral aciclovir in liver transplant recipients when both regimens are given over 100 days (Category 2 statement)

• A 14-day course of intravenous ganciclovir followed by a 106-day course of high-dose oral aciclovir is more effective in reducing the incidence of CMV disease in liver transplant recipients than high-dose oral aciclovir for 120 days (Category 2 statement)

• Oral ganciclovir is more effective than oral aciclovir in preventing CMV disease in kidney transplant recipients (Category 2 statement)

• Intravenous ganciclovir is more effective than CMV immune globulin (CMVIG) in preventing CMV disease in heart transplant recipients (Category 2 statement)

• Intravenous ganciclovir reduces the incidence of fungal superinfection and accelerated atherosclerosis in heart transplant patients (Category 2 statement).

Aciclovir

• Oral aciclovir reduces the incidence of CMV disease in CMV-seropositive and -seronegative renal transplant recipients (Category 1 statement)

• Oral aciclovir reduces the incidence of CMV disease in CMV-seropositive liver transplant recipients but further studies for CMV-seronegative recipients are required (Category 2 statement).

Valaciclovir

• Valaciclovir reduces the incidence of CMV disease in CMV-seropositive and -seronegative kidney transplant recipients (Category 1 statement)

• Valaciclovir reduces the incidence of biopsy-confirmed acute rejection in CMV-seronegative kidney transplant recipients (Category 1 statement)

• In addition to effects on CMV disease, valaciclovir reduces the incidence of diseases caused by HSV or varicella zoster virus (VZV) as well as bacterial/fungal superinfections in CMV-seronegative and -seropositive kidney transplant recipients (Category 1 statement).

CMVIG

• CMVIG reduces the incidence of severe CMV-associated disease (CMV disease in two or more organs) in CMV-seropositive but not in CMV-seronegative liver transplant recipients. Thus, the role of CMVIG monotherapy in the prophylaxis of CMV disease in liver transplant recipients has not been established (Category 1 statement)

• CMVIG reduces the incidence of invasive fungal disease in renal transplant recipients (Category 2 recommendation)

• Non-blinded, randomized trials in liver transplant recipients have shown inconsistent evidence of the benefit of polyvalent immune globulin (IVIG) and CMVIG. Therefore, CMVIG and IVIG cannot be recommended for monotherapy in liver transplant recipients (Category 2 recommendation)

• CMVIG reduced the incidence of CMV disease in kidney transplant recipients in some, but not all, non-blinded, randomized trials. IVIG had no effect on the incidence of CMV disease in kidney transplant recipients. Therefore, CMVIG and IVIG cannot be recommended for monotherapy in kidney transplant recipients (Category 2 recommendation).

Pre-emptive Therapy
Ganciclovir

• Intravenous ganciclovir pre-emptive therapy guided by the shell vial assay is more effective than prophylaxis with high-dose oral aciclovir in liver transplant recipients for the prevention of CMV infection or disease (Category 2 statement).
   

For more information, see the monograph:

The Challenge of CMV Infection and Disease in Transplantation

Prophylaxis
Ganciclovir

• In bone marrow transplant (BMT) recipients, prophylaxis with intravenous ganciclovir administered up to Day 100 post-transplant prevents cytomegalovirus (CMV) infection and disease (Category 1 statement)

• Toxicity of ganciclovir and disease occurring once ganciclovir prophylaxis is stopped are important problems (Category 1 statement).

High-dose intravenous aciclovir

• In BMT recipients, high-dose intravenous aciclovir reduces CMV infection and viraemia but not CMV disease (Category 1 statement)

• In BMT recipients, high-dose intravenous aciclovir improves survival (Category 1 statement).

Cytomegalovirus immune globulin or polyvalent immune globulin

• In BMT recipients, CMV immune globulin (CMVIG) or polyvalent immune globulin (IVIG) cannot be recommended as monotherapy for CMV prophylaxis, although they may be added as adjunctive prophylaxis (Category 2 recommendation).

Pre-emptive Therapy

• In BMT recipients, pre-emptive therapy with intravenous ganciclovir guided by the pp65 antigenaemia assay or polymerase chain reaction (PCR), prevents most cases of CMV disease before day 100 post-transplant (Category 1 statement)

• In BMT recipients, pre-emptive intravenous ganciclovir therapy utilizes less drug than a prophylactic approach and shows less ganciclovir-induced neutropaenia (Category 1 statement)

• In BMT recipients, pre-emptive intravenous ganciclovir therapy strategies guided by the pp65 antigenaemia assay or PCR, reduce the risk of fungal infections compared with ganciclovir prophylaxis (Category 1 statement)

• In BMT recipients, pre-emptive intravenous ganciclovir therapy guided by PCR is more effective in preventing CMV disease and improving survival than pre-emptive therapy guided by the shell vial assay (Category 2 statement).
   

For more information, see the monograph:

The Challenge of CMV Infection and Disease in Transplantation

• Quantitative assessments of cytomegalovirus (CMV) load can aid identification of patients at risk of future CMV disease (Category 2 statement)

• Discrete CMV load thresholds exist, above which the likelihood of disease is high. In order to impact on disease, CMV load should not be allowed to reach high values. The discrete CMV load thresholds, above which the likelihood of disease is high, remain to be determined for each patient type and assay. This validity should be audited at regular intervals, especially in the area of changing immunosuppressive agents (Category 2 statement)

• When using pre-emptive therapy, treatment should be initiated on the basis of early events (initial CMV load and rate of increase of CMV load) during active CMV replication. People in whom viral markers are still positive at the end of a course of treatment are at risk of future disease (Category 2 statement)

• The local turnaround time for an assay must be short to allow the pre-emptive strategy to be useful clinically (Category 2 statement)

• Early initiation of therapy for CMV infection is important as the virus replicates rapidly in the human host (Category 3 statement)

• CMV load measurements have potential for monitoring response to therapy and predicting the time required to reduce CMV load to minimal levels (Category 3 statement)

• For this application, the environment in which the virus is active must be considered (e.g. organ type, level of immunosuppression, duration of transplant) (Category 3 statement)

• If possible, consider reducing the patient’s immunosuppressive drug regimens if there is evidence of CMV infection or disease (Category 3 statement)

• The appearance of viraemia in patients receiving prolonged, low-level antiviral exposure (e.g. from a poorly bioavailable drug) may be a marker of resistant strains (Category 3 statement)

•  A randomized trial is required to determine if patients will benefit overall when duration of therapy is dictated by markers of viral load.(Research need recommendation).
   

For more information, see the monograph:

The Challenge of CMV Infection and Disease in Transplantation

Optimal Thresholds for Guiding Pre-emptive Therapy
pp65 antigenaemia assay

• The threshold values for the pp65 antigenaemia assay were generated from single-centre studies conducted several years ago with different immunosuppressive regimens or haematological procedures (e.g. bone marrow versus stem cells; related versus unrelated donors) (Category 3 statement)

• For the pp65 antigenaemia assay, a threshold of more than 10 positive cells/2x10⁵ cells has been used to guide pre-emptive therapy for solid organ transplant recipients (Category 2 statement)

• For the pp65 antigenaemia assay, a low threshold of e1–2 positive cells/2x10⁵ cells has been used to guide pre-emptive therapy of haematopoeitic stem cell transplant (HSCT) or bone marrow transplant (BMT) recipients (Category 2 statement)

• In the future, molecular assays may replace the pp65 antigenaemia assay in some centres, although both have proven clinical utility (Category 3 statement).

Amplicor CMV Monitor test

• The optimal threshold for the Amplicor CMV Monitor test when using leukocytes needs to be defined for each category of transplant recipient (Research need recommendation)

• The optimal threshold for the Amplicor CMV Monitor test using plasma is approximately 1000–5000 copies/ml for solid organ transplant recipients and is near the limit of detection of the assay for BMT recipients (Category 2 statement).

Frequency of Testing to Guide Pre-emptive Therapy

• Weekly monitoring of cytomegalovirus (CMV) viraemia using the pp65 antigenaemia assay or a molecular method (the best assay has yet to be determined) during the first 3 months after transplantation or longer during intensification of immunosuppression is recommended. Culture or shell vial assay are inadequate for timely pre-emptive therapy (Category 2 recommendation)

• Although molecular methods are slightly more sensitive than the pp65 antigenaemia assay, the choice of test must consider availability (Category 3 recommendation)

• A centre without access to molecular methods or pp65 antigenaemia assays should use prophylaxis rather than pre-emptive therapy for CMV disease prevention (Category 3 recommendation).

Use of Leukocytes versus Plasma Samples

• Assays using leukocytes are more sensitive and more rapidly positive after transplantation than those using plasma or serum (Category 2 statement)

• The utility of leukocytes, plasma or whole blood should be assessed for each diagnostic test and each transplant population (Research need recommendation).